Diagnosis Of Metastatic Disease Research Articles

Clinical implications of Wnt pathway genetic alterations in men with advanced prostate cancer.

Aberrant Wnt signaling has been implicated in prostate cancer tumorigenesis and metastasis in preclinical models but the impact of genetic alterations in Wnt signaling genes in men with advanced prostate cancer is unknown. We utilized the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) clinical-genomic database for this retrospective analysis. Patients with activating mutations in CTNNB1 or RSPO2 or inactivating mutations in APC, RNF43, or ZNRF3 were defined as Wnt-altered, while those lacking such alterations were defined as Wnt non-altered. We compared patient characteristics and clinical outcomes as well as co-occurring genetic alterations according to Wnt alteration status. Of the 1498 patients included, 193 (12.9%) were Wnt-altered. These men had a statistically significant 2-fold increased prevalence of liver and lung metastases as compared with Wnt non-altered patients at the time of initial diagnosis, (4.66% v 2.15% ; 6.22% v 3.07%), first metastatic disease diagnosis (10.88% v 5.29%; 13.99% v 6.21%), and CRPC development (11.40% v 6.36%; 12.95% v 5.29%). Wnt alterations were associated with more co-occurring alterations in RB1 (10.4% v 6.2%), AR (38.9% vs 25.7%), SPOP (13.5% vs 4.1%), FOXA1 (6.7% vs 2.8%), and PIK3CA (10.9% vs 5.1%). We found no significant differences in overall survival or other clinical outcomes from initial diagnosis, first metastatic disease, diagnosis of CRPC, or with AR inhibition for mCRPC between the Wnt groups. Wnt-altered patients with prostate cancer have a higher prevalence of visceral metastases and are enriched in RB1, AR, SPOP, FOXA1, and PIK3CA alterations. Despite these associations, Wnt alterations were not associated with worse survival or treatment outcomes in men with advanced prostate cancer.

Prognostic value of clinical and radiomic parameters in patients with liver metastases from uveal melanoma.

Approximately every second patient with uveal melanoma develops distant metastases, with the liver as the predominant target organ. While the median survival after diagnosis of distant metastases is limited to a year, yet-to-be-defined subgroups of patients experience a more favorable outcome. Therefore, prognostic biomarkers could help identify distinct risk groups to guide patient counseling, therapeutic decision-making, and stratification of study populations. To this end, we retrospectively analyzed a cohort of 101 patients with newly diagnosed hepatic metastases from uveal melanoma by using Cox-Lasso regression machine learning, adapted to a high-dimensional input parameter space. We show that substantial binary risk stratification can be performed, based on (i) clinical and laboratory parameters, (ii) measures of quantitative overall hepatic tumor burden, and (iii) radiomic parameters. Yet, combining two or all three domains failed to improve prognostic separation of patients. Additionally, we identified highly relevant clinical parameters (including lactate dehydrogenase, thrombocyte counts, aspartate transaminase, and the metastasis-free interval) at first diagnosis of metastatic disease as predictors for time-to-treatment failure and overall survival. Taken together, the risk stratification models, built by our machine-learning algorithm, identified a comparable and independent prognostic value of clinical, radiological, and radiomic parameters in uveal melanoma patients with hepatic metastases.

Focal leptomeningeal vascular anomalies on brain MRI: A mimic of leptomeningeal metastatic disease

Abstract Background The diagnosis of leptomeningeal metastatic disease has major prognostic and therapeutic implications. We report 13 patients with a radiologically distinct kind of focal, enhancing leptomeningeal lesion on brain MRI that mimics leptomeningeal metastatic disease. Methods These patients were assessed at University Health Network (Toronto, Canada) between January 2001 and December 2023. Results Median age was 68 years (range, 55–78 years) and 10 patients were women. All patients had brain magnetic resonance imaging (MRI) including contrast-enhanced T2-weighted fluid attenuation inversion recovery (FLAIR) and T1-weighted spin echo sequences. MRI in all 13 patients showed a focal enhancing lesion located along the leptomeningeal surface of the brain. The MRI exams were reported as possible or likely leptomeningeal metastatic disease for the majority (9/13) of patients. Each lesion was curvilinear rather than sheet-like, and some lesions consisted of multiple connected/branching curvilinear structures with the appearance of abnormal vessels. The lesions were distinct from normal blood vessels. Some lesions had a visible connection with a nearby cortical vein. Follow-up contrast-enhanced brain MRI for 8/13 (62%) patients at a median of 3.9 years (IQR 2.4–6.6 years) showed all lesions were unchanged over time. Another 2/13 (15%) patients had clinical and CT brain follow-up after one year with no evidence of metastatic disease. Conclusions We describe a distinct kind of focal, enhancing leptomeningeal lesion on brain MRI that mimics metastatic disease. These lesions are likely a type of low-flow vascular anomaly. Their curvilinear/branching shape and intense enhancement particularly on T2-weighted FLAIR images distinguish these lesions from tumors.

Claims-based analysis of treatment practices of patients with metastatic gastroenteropancreatic neuroendocrine tumors (mGEP-NET) in the USA.

e16286 Background: GEP-NET is a rare disease with variable tumor biology. An indolent disease course with subtle symptoms renders timely diagnosis difficult; 2/3 of patients (pts) are diagnosed at locally advanced or metastasized stage. In clinical decision-making, disease-specific factors, patient (pt) age and long-term disease control must be balanced against the aggressiveness of therapies. NCCN, NANETS and ENETS guidelines recognize the diversity of mGEP-NET by recommending individualized treatment approaches. We aimed to describe treatment (Tx) utilization patterns in mGEP-NET. Methods: Retrospective cohort study using MarketScan® Commercial and Medicare Databases spanning 07/01/2017-01/31/2023. Eligible were GEP-NET pts with ≥1 inpatient or ≥2 outpatient claims, a subsequent new diagnosis of metastatic disease (index), no secondary malignancy, and follow-up time of ≥12 months (m) after index. Results: Of 16218 GEP-NET pts, 2002 (mean age 60y; 50% female) met inclusion criteria. Mean follow-up time after index was 17m, with 49%, 27% and 15% followed up for ≥12, 24 and 36m, resp. Medical history (12m baseline before index) included mean Charlson Comorbidity Index of 2.62, with hypertension (HTN), type 2 diabetes (T2DM), chronic liver disease (CLD), asthma/COPD, cardiovascular disease (CVD), and chronic kidney disease (CKD) present in 56, 26, 22, 18, 17 and 10% of pts, resp.; 5% had carcinoid syndrome. In total, 949 pts (47.4%) received first-line (1L) systemic Tx: somatostatin analogs (SSA; 61.6%) of either very short or long duration (median 116d vs 775d), chemotherapy (38.8%), targeted therapies (3.4%) and PRRT (0.5%). Relative to NCCN cancer surveillance guidelines, 49.5% received more and 36.8% received fewer than 4 scans in the first year of treatment. Conversely, 1053 (52.6%) did not receive any 1L systemic Tx. With the exception of CLD, pts with vs without 1L Tx had similar proportions of medical conditions during the 12m baseline and during follow-up (HTN 72.4 vs 66.5%; T2DM 34.0 vs 30.3%; asthma/COPD 16.5 vs 19.3%; CVD 27.3 vs 36.9%; CKD 18.9 vs 17.9%; however, CLD 54.0 vs 36.7%). See Table comparing both cohorts on insurance, treatments, and health care utilization during follow-up. Conclusions: This claims analysis reveals treatment differences among mGEP-NET pts that cannot be explained by the parameters assessed herein. Further research should investigate factors influencing diagnosis and treatment decision-making, applying also pt-level health record data; and analyze economic barriers to diagnosis and treatment. [Table: see text]

Utilization of TAS-102 (TAS) or regorefenib (Rego) among commercially insured refractory metastatic colorectal cancer (R-mCRC) patients.

e23121 Background: R-mCRC is the time period after use of fluoropyrimidine, oxaliplatin, and irinotecan and usually in conjunction with biological therapies. Several agents are efficacious during R-mCRC with high level evidence for survival improvement. We describe access and utilization of therapeutics in this state using claims data. Methods: This is a retrospective cohort study using the Optum’s de-identified Clinformatics® Data Mart Database (2013-2020). We identified patients (pts) with mCRC after 2014; the metastasis date was set as the index date. Pts were required to have a continuous enrollment for 6 months pre- and 18 months post-index to ensure they were potentially in the refractory setting. Eligible pts were required to have utilization of standard therapies after diagnosis of metastatic disease. Those who switched from FOLFOX to FOLFIRI or vice versa were classified as refractory. The use of either TAS or Rego was identified during the entire follow-up period. Baseline characteristics were compared between patients who received TAS or Rego and those who did not using Chi-Squared test/T-test. We conducted multivariate logistic regressions to evaluate the factors associated with patients’ access to TAS or Rego. Results: 6,233 pts with mCRC identified, 53.7% male, and 70.4% white. FOLFOX was the dominant treatment in the 1L setting (60.1%). 9.7% received either TAS or Rego, with 4.8% taking Rego first and 4.9% receiving TAS first. Recipients of TAS or Rego were younger (mean age of 62.8 vs. 66.5, p < 0.001) and had fewer comorbidities (e.g. myocardial infarction was associated with reduced probability of receiving either TAS or Rego (p < 0.05)). More were enrolled in preferred provider organization in pts using these agents (45% vs. 37.5%, p < 0.001). In the multivariate analysis, Asian pts had a higher likelihood of using late-line therapies (OR = 1.53, p < 0.05). Among 707 pts who switched from FOLFOX to FOLFIRI or vice versa (R-mCRC), 29.8% received late-line therapy (15.7% TAS followed by Rego). The trends were similar among these patients. The TAS or Rego recipients were younger than the non-recipients (mean age of 60.6 vs. 63.8, p < 0.001), had fewer comorbidities, and enrolled in preferred provider organization (47.5% vs. 38.5%, p < 0.05). Conclusions: While front line therapy for mCRC is relatively homogenous, there is significant heterogeneity in transitioning and receiving later lines of therapy. This claims level analysis highlights the disparities in access to later lines of therapy. Further analyses for characterization of the patterns of care and disparities are underway.

Correlation between metastatic site and immunotherapy efficacy in patients with advanced dMMR/MSI colorectal cancer: Real-World Italian multicentric retrospective study (Colon-MSI).

e15544 Background: Immune checkpoint inhibitors (ICIs) are the gold standard therapy in metastatic colorectal cancer (mCRC) patients (pts) with microsatellite instability (MSI). The Colon-MSI study aimed to describe a cohort of MSI mCRC pts treated with ICIs before Italian pembrolizumab approval and to evaluate the efficacy, safety, and possible predictive factors of response in a real-world setting. Methods: We retrospectively collected data of pts with MSI mCRC treated with ICIs before June 30, 2023, in 16 Italian Cancer Centers. The OS was calculated from the diagnosis of metastatic disease, and the PFS from the beginning of ICIs. We explored the correlation between clinicopathological factors, survival outcomes, and treatment response. Results: Between January 2021 and June 2023, we reported 83 consecutive pts with data available. Among all, the median age was 61 years (23-86), 42 (51%) were female, and 45 (54%) had a ECOG PS 0; 35 (42%) pts were at stage IV at diagnosis, and 61 (74%) had right colon tumor site. The most common metastatic sites were liver (35%), lymph nodes (43%), peritoneum (31%), and lung (15%); 48 (58%) pts had a single metastatic site. 33 (39%) pts had a mucinous adenocarcinoma, 32 (39%) BRAF mutated, 32 (39%) RAS mutated, and 26% presented a Lynch syndrome. The majority of pts (69%) were pre-treated, and 26 pts (31%) received ICIs in first line. Nivolumab alone or plus Ipilimumab, and Pembrolizumab, were administered in 23 (28%), 3 (4%), and 57 (68%) pts, respectively. The median follow-up was 23 (1-65) months (m) and the median duration of treatment was 23 m (0-65) with 27 pts still ongoing. Treatment-related severe toxicities (G3 or G4) were observed only in 5.6% of pts. The median OS and PFS were not reached; the mean OS was 45.6 m (IC 95% 39.6-51.6) and the mean PFS was 38.8 m (IC 95% 32.5-45.1). Complete response (CR) was observed in 20 pts (24%), partial response (PR) in 28 (34%), stable disease (SD) in 19 (23%) and progression disease (PD) in 16 (19%). Overall response (ORR) was observed in 48 pts (57.8%; 95 %IC 0.31- 0.53), and disease control rate in 67 pts (80.7%; 95% IC 0.11– 0.29). Lung metastatic site was associated with poorer outcome in terms of OS (p = 0.001, HR 3.88 IC 95% 1.7-8.9), PFS (p = 0.045 HR = 2.31 IC95% 1-5.2), and ORR (p = 0.015 OR = 6.19 IC95% 1.4-26.9). Significantly worse PFS was also observed in pts with liver metastasis (p = 0.009 HR = 2.5 IC 95% 1.3-4.9). Conclusions: Our data confirm that ICIs are effective and well-tolerated treatment in MSI mCRC pts, with long-term clinical outcomes reported. These results suggest an unfavorable correlation between lung and liver metastasis and the ICI response. Further biomolecular analysis will be provided in the future.

Stereotactic radiosurgery (SRS) for non-small cell lung cancer (NSCLC) in the oncogene-addicted era: A real-world UK tertiary center experience.

e14011 Background: 30-50% of NSCLC patients develop brain metastases (BM). Re-evaluation of the role of SRS is required with evolving understanding of molecular subtypes of NSCLC and increasing intracranial efficacy of systemic agents. Methods: We conducted a retrospective analysis of NSCLC patients receiving SRS at our centre from 05/16-11/23. Primary objective was median overall survival (mOS months). Analysis was performed on Prism 10.1.1. Multivariate analysis was conducted using Cox Proportional Hazards Regression, with age, gender, KPS, BM size, total BM volume and oncogene status as predictor variables. Extraction from medical records was undertaken by authors, with local R&D committee approval. Results: 237 patients were evaluable. 59% (N=139) were oncogene-addicted (oNSCLC) and 41% (N=98) non-oncogene-addicted (non-oNSCLC). Median duration of follow up was 43.3m. m OS was 11.9m overall. For oNSCLC mOS was 13.1m vs 8.8m for non-oNSCLC (HR 1.49, P=0.02). mOS was 20.7m for EGFR sensitizing NSCLC (N=48) vs 10.5m without (HR 1.40 P=0.12). mOS for ALK+ (N=22) was 29.3m vs 11.6m for non-ALK+ (HR 1.90, P=0.05). mOS for KRAS+ (N=32) was 11.6m vs 12.0m without (HR 0.91, P=0.68). Significantly inferior mOS was seen for single (N=186 [78%]) vs multiple (N=51[22%]) SRS courses (8.4m vs 38.8m, [HR 0.34 P=<0.0001]). SRS at diagnosis of BM (N=118) had a mOS of 12.3m vs at nadir (N=9, not reached [HR0.44, P=0.18]), progression on 1st line TKI (N=31, 22.1m [HR 1.1, P=0.79]) and at any other time (N=157, 7.8m [HR 1.33, P=0.11 ]). There was no significant difference in survival for patients diagnosed with brain metastases at the diagnosis of metastatic disease compared to those who developed brain metastases during their disease course (12.3m vs 10.6m [HR 1.18, P=0.33]). Survival of those with 1 site of metastatic disease (18.3m) was numerically improved compared to those with 2 (10.7m, HR 1.26, P=0.25) sites, and statistically significant compared to those with 3 (10.1m, HR 1.69, P<0.02) and ≥4 (4.4m, HR 4.41, P<0.0001) sites. Conclusions: Median OS in oNSCLC was superior to non-oNSCLC, driven by numerically superior survival in EGFR+ and ALK+ cohorts. Significantly improved OS was observed in patients with multiple vs single SRS treatments, however this may be confounded by biases. Patients treated with SRS at nadir had numerically superior OS to those treated at other timepoints, however this must be interpreted with caution due to small sample size. Further prospective research is needed to interrogate these findings and guide local therapies in NSCLC with BM. [Table: see text]

E.1 Focal leptomeningeal vascular anomalies on brain MRI: a mimic of leptomeningeal metastatic disease

Background: The diagnosis of leptomeningeal metastatic disease has major prognostic implications. We report 13 patients with a radiologically distinct, focal, enhancing leptomeningeal lesion on brain MRI mimicking leptomeningeal metastatic disease. Methods: These patients were assessed at University Health Network between January 2001 and December 2023. Results: Median age was 68 years and 10 patients were women. All patients had brain MRI including contrast-enhanced T2-weighted FLAIR and T1-weighted spin echo sequences. MRI in all patients showed a focal enhancing lesion along the leptomeningeal surface of the brain. The MRI exams were reported as possible metastatic disease for the majority (9/13) of patients. Each lesion was curvilinear rather than sheet-like, and some consisted of multiple connected/branching curvilinear structures with the appearance of abnormal vessels. Some lesions had visible connection with a nearby cortical vein. The lesions were distinct from normal blood vessels. Follow-up contrast-enhanced brain MRI for 8/13 patients at a median of 3.9 years showed all lesions were unchanged over time. Conclusions: We describe a distinct kind of focal, enhancing leptomeningeal lesion on brain MRI that mimics metastatic disease. These lesions are likely a type of low-flow vascular anomaly. Their curvilinear/branching shape and intense enhancement particularly on T2-weighted FLAIR images distinguishes these lesions from tumor.

The prognostic value of immune-nutritional status in metastatic colorectal cancer: Prognostic Nutritional Index (PNI)

Backround and purposeA low Prognostic Nutritional Index (PNI) value, which reflects immune nutrition and inflammation around the tumor, is associated with an unfavorable prognosis, and it was aimed to reveal its prognostic value in metastatic colorectal cancer (CRC).MethodsIn our retrospective cross-sectional study, patients with a diagnosis of metastatic colorectal disease without active infection, between January 2010 and December 2016 were included. The PNI values at the time of diagnosis were calculated according to the formula (10 × serum albumin (g/dL)) + (0.005 × total lymphocyte value).ResultsThe mean PNI value of 253 patients included in the study was 46.6. While 53.75% (n = 136) of the patients had a PNI value of 46.6 and above, 46.25% (n = 117) had a PNI value below 46.6. The overall survival (OS) of the group with a PNI of 46.6 and above was statistically significantly longer (53.06 months vs 38.80 months, p = 0.039). The PFS duration of the group with PNI below 46.6 was 25.66 months, while the PFS duration of the group with PNI above 46.6 was not reached (p = 0.265).ConclusionPNI is a simple and inexpensive index that evaluates the immunonutritional status, and it is a prognostic marker that can be easily used in patients with metastatic colorectal cancer as in other cancer types.

Abstract PS11-02: Clinical risk factors of Central Nervous System (CNS)-related death in patients with HER2-positive metastatic breast cancer

Abstract Background: Central nervous system (CNS) relapse represents a challenge in the management of patients with HER2-positive (+) metastatic breast cancer. Data regarding the impact of brain metastases (BrM) and CNS involvement on mortality are sparse. In this study we sought to determine the proportion of HER2+ MBC patients in which CNS disease is the cause of death and identify risk factors associated with CNS-related mortality. Methods: We reviewed medical records of 294 consecutive patients with HER2+ MBC and diagnosis of CNS disease including parenchymal BrM, leptomeningeal disease (LMD) or dural metastases (DM), treated at Memorial Sloan Kettering Cancer Center between August 2010 and April 2022. HER2-positivity was assessed at the first diagnosis of metastatic disease (any site). Clinicopathologic characteristics including disease burden at presentation, timing of CNS disease and extracranial metastases (ECM), neurologic complications, and local and systemic treatments were collected. CNS-related death was defined as any death caused by BrM or LMD or DM progression or CNS treatment-associated complications. CNS-related death was estimated using cumulative incidence in the competing risks setting (with death due to other causes as a competing event) and overall survival (OS) was estimated using Kaplan Meier methodology. Risk factors associated with CNS-related death were assessed using sub-distribution hazards regression modeling. Treatments given after CNS disease diagnosis were treated as time-varying variables. Tests were two-sided with statistical significance < 0.05. Results: After excluding 19 patients (11 for discordant HER2 status, 5 for concomitant second solid tumor, and 3 for missing data), 275 patients were included in these analyses (258 patients with parenchymal BrM +/- LMD, 8 patients with DM only, 2 patients with DM concomitantly with LMD, and 6 patients with LMD only). Overall, 63/275 (23%) presented with CNS as first and only site of metastasis, 210 (76%) patients developed CNS disease synchronously with or following ECM, and 2 had unknown timing. 125/275 (45%) had de novo MBC, and nearly all patients were treated with CNS local therapies (92% ≥1 radiation treatment and 28% underwent ≥1 BrM resection). The median number of lines of systemic therapy after CNS disease diagnosis was 1 (range: 0-14); 105/275 (38%) patients received a HER2 tyrosine kinase inhibitor (lapatinib: 21%, neratinib: 4.4%, and tucatinib: 12%). The median follow-up was 3.6 years for survivors (range: 0.22 years-12 years). 193/275 (70%) patients died, of whom 105 (54%) died of CNS-related cause. The 3-year OS rate was 40% (95% CI=34%-46%), which varied for patients with BrM only at the diagnosis of metastatic disease [56% (95% CI=43%-69%] compared to patients with ECM +/- BrM [35% (95% CI=28%-42%] (p=0.05). The cumulative incidence of CNS-related death at 3 years was 33% (95% CI=27%-39%). Upon univariable modeling, LMD and CNS radiation treatment (RT) were associated with CNS-related death, and these associations remained statistically significant in a multivariable model [LMD: HR=2.49 (95% CI=1.62-3.83), p< 0.0001, and RT: HR=2.91 (95% CI=1.27-6.64), p=0.01]. Conclusions: Greater than half of patients with HER2+ with CNS involvement suffered of CNS-related death, with greatest risk among patients with LMD. We hypothesize that the association between radiotherapy and CNS-related death may reflect upfront response to systemic cancer-directed treatments of those in patients with DM only or limited CNS disease extension. CNS-only relapse at metastatic presentation portended improved survival than intra- plus extracranial progression, supporting an approach of aggressive local therapy for selected patients. Multimodality approaches using HER2-directed agents effective against parenchymal BrM, LMD along with extracranial metastases, in combination with local CNS-directed therapies need to be optimized. Citation Format: Emanuela Ferraro, Rabih Bou Nassif, Anne Reiner, Samantha Brown, Umberto Tosi, Katherine Panageas, Chau Dang, Andrew D Seidman, Nelson Moss. Clinical risk factors of Central Nervous System (CNS)-related death in patients with HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS11-02.

Abstract PO4-04-14: Change of first-line treatment pattern in metastatic luminal breast cancer: Results from the Austrian AGMT_MBC-Registry

Abstract Background: For patients with HR+/HER2- (luminal) metastatic breast cancer (MBC), international guidelines recommend endocrine-based first-line therapy [ET] in combination with a CDK4/6 inhibitor for most patients. Only for patients with imminent organ failure, first-line chemotherapy should be considered. To clarify changing patterns of first-line treatments over time in an Austrian population of luminal MBC patients, we analyzed the data from the MBC registry of the Austrian Study Group for Medical Tumor Therapy (AGMT-MBC-Registry). Methods: The AGMT-MBC-Registry is an ongoing multicenter registry for MBC patients in Austria. Only patients with luminal MBC and sufficient outcome data were included in this analysis. Patients were assigned to one of the following groups according to the year of start of first-line treatment for MBC: 2001-2010, 2011-2013 (no CDK4/6i available for first-line in both periods), 2014-2016 (CDK4/6i available in early access programs and clinical trials for first-line only), 2017-2019, and 2020-2022 (CDK4/6i available in both periods). Time to first chemotherapy (TTC) defined as start of first-line treatment until first application of a cytotoxic agent, and overall survival (OS) defined as start of first-line treatment until death were calculated by the Kaplan-Meier method and compared using the log-rank test. OS analysis was adjusted for disease free survival (DFS) category (de novo, DFS < 24 month, DFS ≥ 24 month), menopausal status (pre-, postmenopausal, unknown), age at diagnosis of metastatic disease (continuous), number of metastatic sites at diagnosis (1, 2-3, > 3), visceral disease (no, yes), and Charlson comorbidity index at diagnosis (continuous). Results: As of May 16th 2023, 1,330 patients with HR+/HER2- disease receiving at least one treatment-line for MBC were evaluable. First-line treatments significantly changed over time (P < 0.001). In patients diagnosed between 2001 and 2010, 61.4% were treated with first-line chemotherapy compared to 10.0% in patients diagnosed between 2020 and 2022 (Table 1). Additionally, TTC also significantly increased over time (P < 0.001; Table 2). In contrast, the proportion of patients treated with a first-line CDK4/6i plus endocrine therapy combination increased over time from 4.4% in 2014-2016 up to 75.5% in the period of 2020-2022. Additionally, adjusted median overall survival estimates significantly increased over time (P < 0.001; Table 2). Conclusion: In our registry, the proportion of patients with luminal MBC treated with first-line chemotherapy significantly decreased over time, whereas the proportion or patients treated with first-line CDK4-6 inhibitors significantly increased. This is in line with the change of guideline recommendation as well as the availability of CDK4-6 inhibitors over the last 2 decades. The availability of new treatment options has significantly increased median overall survival over time. Table 1: First-line treatment pattern over time Period N ET ET plus CDK4/6i Chemotherapy Others* 2001-2010 220 84 (38.2%) 0 (0.0%) 135 (61.4%) 1 (0.5%) 2011-2013 238 116 (48.7%) 0 (0.0%) 110 (46.2%) 12 (5.0%) 2014-2016 318 174 (54.7%) 14 (4.4%) 99 (31.1%) 31 (9.7%) 2017-2019 293 60 (20.5%) 190 (64.8%) 36 (12.3%) 7 (2.4%) 2020-2022 249 22 (8.8%) 188 (75.5%) 25 (10.0%) 14 (5.6%) Overall 1,318 456 (34.6%) 392 (29.7%) 405 (30.7%) 65 (4.9%) Legend: N - number of patients, ET - endocrine therapy (tamoxifen, aromatase inhibitor and/or fulvestrant), CDK4/6i - CDK4/6 inhibitor; * e.g. endocrine treatment plus everolimus or investigational study treatment Table 2: Time to first chemotherapy (TCC) and overall survial (OS) over time Period Median TTC [months] Adjusted median OS [months] 2001-2010 0.0 (0.0 - 0.0) 49.4 (41.2 - 56.6) 2011-2013 4.3 (0.0 - 13.8) 48.2 (38.3 – 69.7) 2014-2016 20.0 (14.0 - 26.4) 60.3 (50.2 - 77.5) 2017-2019 40.1 (33.3 - 59.8) 60.8 (52.8 - NR) 2020-now 30.4 (27.6 - NR) NR (NR - NR) Legend: N - number of patients, NR - not reached Citation Format: Gabriel Rinnerthaler, Simon Gampenrieder, Angelika Pichler, Walter Herz, Andreas Petzer, Renate Pusch, Marija Balic, Christoph Suppan, Sonja Heibl, Lukas Scagnetti, Margit Sandholzer, Clemens Schmitt, August Zabernigg, Daniel Egle, Petra Pichler, Christopher Hager, Florian Roitner, Johannes Andel, Kathrin Strasser-Weippl, Rupert Bartsch, Michael Hubalek, Michael Knauer, Christian F. Singer, Richard Greil. Change of first-line treatment pattern in metastatic luminal breast cancer: Results from the Austrian AGMT_MBC-Registry [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-14.

Abstract PO1-14-10: Comprehensive clinicogenomic characterization of inflammatory breast cancer

Abstract BACKGROUND: Inflammatory breast cancer (IBC) is a rare type of breast cancer associated with a unique clinical presentation and overall poor outcomes, recognized as a distinct category by the AJCC staging system. The biological mechanisms driving the IBC phenotype are relatively undefined—partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts. Here, we report one of the largest, subtype-informed clinicogenomic characterizations of IBC to date. METHODS: A retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing (OncoPanel, up to 447 cancer-associated genes) was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between IBC and non-IBC cases. Median follow-up was 28.1 months. RESULTS: Our profiled cohort included 140 patients with IBC specimens (n = 68 primary tumors, 72 metastatic tumors) and 2317 patients with non-IBC specimens (n = 702 primaries, 65 local recurrences, 1550 metastases). Of these, 87.4% of patients were White, 4.7% Black, 3.6% Asian or Pacific Islander, and 4.3% other/unknown. Clinicopathologic differences between IBC and non-IBC cases were consistent with previous reports—including younger age at diagnosis of metastatic disease (51 vs 54 years, p = 0.04), and a higher proportion of grade 3, estrogen receptor-negative and HER2-positive tumors (p < 0.001). Among the hormone-receptor (HR)-positive subtype, IBC tumors showed a significant enrichment in Luminal B (LumB)-inferred disease (62.5% vs 39.8%, p < 0.005), defined as tumors with grade 3 or progesterone receptor staining < 10%. The most recurrent somatic alterations spanning all subtypes in IBC were TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%) and GATA3 (8%). A multivariate logistic regression analysis accounting for HR and HER2 status revealed a significant enrichment in TP53 SNVs in IBC vs non-IBC (OR 2.08 [95% CI 1.34-3.24], adjusted p-value 0.04). Frequency of TP53 alterations in IBC vs non-IBC cases was 85.1% vs 64.3% in HER2-positive and 50.0% vs 27.7% in HR-positive disease—with an enrichment of TP53 mutations in IBC LumB-inferred tumors vs non-LumB (64% vs 26%, p < 0.05). When comparing HR+ IBC LumB vs HR+ non-IBC LumB cases, TP53 mutations were again enriched (p < 0.05)—suggesting LumB-like histopathology is not the only driving feature of TP53 enrichment in HR+ IBC. TMB did not differ substantially between IBC and non-IBC and no other statistically significant enrichments were observed, including when grouping mutations into six canonical cancer pathways (cell cycle, Notch signaling, PI3K pathway, RTK/RAS signaling, TP53 pathway and WNT signaling). CONCLUSIONS: Taken together, this study provides a comprehensive landscape of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC. Our data support a lack of major genomic differences other than enrichments in TP53 mutations and an associated LumB-like histopathology. These results both reinforce the importance of TP53 mutations in IBC biology and suggest additional analyses beyond somatic DNA-level changes are warranted. Future efforts with the DFCI IBC cohort will assess germline-somatic interactions, non-genomic or transcriptomic characterizations, and potential environmental influences to better understand the mechanisms driving this unique disease. Citation Format: Nolan Priedigkeit, Beth Harrison, Melissa Hughes, Robert Shue, Yvonne Li, Gregory Kirkner, Claire Remolano, Sarah Strauss, Janet Files, Anne-Marie Feeney, Ayesha Mohammed-Abreu, Ana Garrido-Castro, Romualdo Barroso-Sousa, Brittany Bychkovsky, Faina Nakhlis, Jennifer Bellon, Tari King, Bruce Johnson, Lynette Sholl, Deborah Dillon, Beth Overmoyer, Sara Tolaney, Andrew Cherniack, Nancy Lin, Filipa Lynce. Comprehensive clinicogenomic characterization of inflammatory breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-14-10.

Abstract PO4-15-05: Genomic characterization and molecular predictive biomarkers for chemotherapy in a real-world population with metastatic triple-negative breast cancer

Abstract Background: The genomic landscape of metastatic triple-negative breast cancer (mTNBC) in a real-world population is poorly defined and despite recent advances in precision oncology, molecular biomarkers for chemotherapy are largely lacking. The presence of specific genomic alterations and alterations in oncogenic pathways have the potential to provide prognostic as well as predictive information for chemotherapy, which remains the backbone treatment strategy for mTNBC. Methods: We conducted next-generation sequencing (NGS) with the FoundationOne CDx panel on tissue from the primary tumor and/or metastasis of 112 consecutive patients with mTNBC that were treated between 1998 and 2019 at 4 different Swedish hospitals. Every genomic alteration was, if applicable, subdivided into 1 of 10 canonical oncogenic pathways and noted for its involvement in the homologous recombination pathway (HRP). Frequently altered genes and pathways were then correlated with overall survival (OS) and evaluated regarding their association with progression-free survival (PFS) and response rate (RR) in patients treated with different chemotherapy agents. Tumor samples of patients with rapid progression or exceptional response to chemotherapy underwent exploratory comparison with regards to frequently altered genes and pathways and known clinical prognostic factors were compared between the two patient groups. Results: After excluding 15 patients due to insufficient quantity/quality of tumor tissue or absence of clinical data, 97 patients were analyzed. The median age at diagnosis of metastatic disease was 61 (range: 28-90), 80 % had visceral disease and 26 % received platinum-based chemotherapy in the first line setting. The most frequently altered genes were: TP53 (82 %), RAD21 (25 %), PIK3CA (23 %), MYC (22 %) and BRCA 1 or 2 (16 %). The most frequently altered pathways were TP53 (86 %), PI3K (60 %), RTK/RAS (47 %) and cell cycle (36 %). In total, 26 % of patients had an alteration in the HRP. None of the most frequently occurring genomic alterations were associated with OS. Variants of clinical significance in the HRP and BRCA1/BRCA2 genes were associated with a longer PFS in patients treated with platinum-based chemotherapy in the first line setting (HR 0.12-0.84 and 0.12-0.92). Exceptional responders to chemotherapy exhibited a more favorable clinical profile than rapid progressors (median age 51.5 vs 66.5, median Charlson comorbidity index 0.5 vs 3) whereas some numerical difference in the genomic profiling in terms of genomic alterations in MYC and RAS/RTK pathways (more often in exceptional responders) could be observed. Conclusions: We found no genomic alteration with prognostic significance in a cohort of mTNBC patients treated with chemotherapy in a real-world setting. Somatic variants of clinical significance in BRCA 1 and 2 and other HRP-related genes seem to define subgroups of patients with mTNBC that respond favorably to platinum-based chemotherapy. Further research into the genomic landscape of tumors from patients with rapid progression or exceptional response to specific treatment strategies can provide insights into mechanisms of resistance and identify new predictive biomarkers. Citation Format: Erik Olsson, Henrik Lindman, Evangelos Digkas, Viktoria Thurfjell, Haidar Mir Ali, Ute Krüger, Anna-Karin Wennstig, Marie Sundqvist, Antonis Valachis. Genomic characterization and molecular predictive biomarkers for chemotherapy in a real-world population with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-05.

Abstract PO4-05-11: Effects of body mass index on the treatment outcome of patients with metastatic breast cancer in the real world

Abstract Purpose: Metastatic/recurrent breast cancer has a relatively long survival compared to other cancers and depending on the biologic subtype, the treatment outcome is different. In general, obesity or overweight is associated with poor prognosis of breast cancer, but the relationship between body mass index (BMI) and prognosis in metastatic cases is not clear. The aim of this study is investigating the effect of BMI on survival outcome through long-term follow-up in single institution, retrospectively. Method: This study included the patients with metastatic/recurrent breast cancer who has been diagnosed from January 2000 to December 2022 in an institution. BMI was calculated based on weight at diagnosis of metastatic disease, divided into 4 groups according to Asian-Pacific classification, and clinical characteristics including biologic subtype and overall survival (OS) were retrospectively reviewed. The statistical analysis was performed using Kaplan-Meier survival analysis and Cox proportional hazard model. Result: A total of 679 patients were enrolled. Median age was 51 years-old (25~89), 672 patients (99.0%) were female and 425 patients (62.6%) showed pre-menopausal status. The frequencies of HR+, HER2, and TNBC subtype were 335 (50.7%), 191 (28.9%), and 135 (20.4%), respectively and the BMI classification was 33 (5.5%), 251 (41.6%), 124 (20.5%), 196 (32.4%) for underweight, normal, overweight, and obesity, respectively. During a median follow-up of 33.8 months, the median OS in each of the HR+, HER2+, and TNBC subgroups was 54.9 (95% CI 38.7-71.1), 62.8 (95% CI 47.8-77.8), and 20.8 months (95% CI 12.0-29.7). In univariate analysis, there was no statistically significant difference in OS according to BMI in whole patients, however, in the HER2-positive group, the underweight BMI group showed poor OS (p=0.045). In multivariate analysis, the factors affecting OS were age (HR 0.59, 95% CI 0.41-0.87, p=0.008), poor ECOG PS (HR 8.35, 95% CI 2.54-27.49, p< 0.001), TNBC subtype (HR 2.14, 95% CI 1.56-2.94, p< 0.001), visceral metastasis (HR 2.13, 95% CI 1.63-2.79, p< 0.001), 5% or more weight loss during treatment (HR 1.46, 95% CI 1.09-1.97, p=0.012) and obesity BMI group (HR 0.69, 95% CI 0.51-0.94, p=0.019). Conclusion: In the case of patients with metastatic/recurrent breast cancer, there is concern about an increase in body weight, a known risk factor for breast cancer, while receiving palliative aim treatment. For the past 20 years, the mainstay of treatment for metastatic/recurrent breast cancer has been cytotoxic chemotherapy or anti-HER2 agents, and in this case, the higher BMI group patients showed better treatment outcomes compared with normal BMI patients. Citation Format: Kyoung Eun Lee, Ahrong Ham, Sewon Lee, Jungmin Jo, Soo Ji Hong, Ji Eun Lee, Haena Lee, Sungchan Gwark, Jeongshin An, Hyun-Goo Kim, Jun Woo Lee, Joohyun Woo, Woosung Lim, Byung-In Moon, Sei Hyun Ahn, Hye Ah Lee. Effects of body mass index on the treatment outcome of patients with metastatic breast cancer in the real world [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-05-11.

Abstract PO5-13-12: Personalized circulating tumor DNA testing for recurrence detection and treatment response monitoring in patients with metastatic invasive lobular carcinoma

Abstract Introduction Metastatic invasive lobular carcinoma (mILC) presents unique challenges during treatment response monitoring. A higher frequency of metastases to the bone, gastrointestinal tract, uterus, meninges, ovary, and diffuse serosal involvement is observed in mILC. The challenge with mILC is that they can be difficult to detect clinically and radiographically, and consequently clinical progression can be difficult to determine with conventional imaging modalities like CT Scans, thus precluding many patients with mILC from enrolling into clinical trials. Therefore more accurate biomarkers are needed to better assess response to treatment in real time. In this study, we demonstrate the feasibility of longitudinal ctDNA testing for treatment response monitoring in patients with mILC. Methods In this real-world study, longitudinal plasma samples (n=219) from 60 patients with mILC, treated across 52 independent clinics between 7/22/21 and 6/15/23, were analyzed. A personalized, tumor-informed ctDNA assay (SignateraTM bespoke, mPCR-NGS assay) was used for detection and quantification of ctDNA in plasma samples. Results In this cohort, the median patient age at diagnosis of metastatic disease (baseline) was 62.9 years (range: 32.2-79.7). Of the 60 patients, 41 (68%) had ER+PR+HER2-, 7 (12%) ER+PR-HER2-, 4 (7%) ER+PR+HER2+, 2 (3%) ER+PR-HER2+, 1 (2%) triple negative breast cancer; receptor status was not available for 5 (8%) patients. CDH1 (75%) and PIK3CA (42%) were observed to be the top two genes with somatic, nonsynonymous mutations. Mutations in TP53 and TBX3 were observed in 13% of patients, mutations in AKAP9, IGFN1, RBM26, and RFC3 in 10% of patients, and mutations in ESR1 in 6.7% of patients. At variant level, PIK3CA p.H1047R (22%) and RBM26 p.Q701Tfs*23 (10%) were the top two somatic variants identified. The most common CDH1 variant, p.Q23*, was found in 5% of the cases. Of the 60 patients, 37 (61.7%) were ctDNA-positive at all time points while on treatment (chemotherapy/endocrine therapy/targeted therapy) with the first time point collected at a median of 6.7 months (range: 2.5-2307 months) from baseline. Of these 37, imaging/biopsy results after baseline were available for 32 patients, 86% (27/32) of whom progressed. Thirty-two of 37 persistently ctDNA-positive patients had serial ctDNA measurements available, of which 14 (43%) had significant increase in ctDNA levels (average: 47-fold increase, standard deviation: 98) from first to last time points. At some point during their care ctDNA was detectable in all (n=51) patients with evidence of clinical progression. Of the 60 patients, 14 (23.3%) were ctDNA-negative at all time points tested. None of the 14 persistently ctDNA-negative patients had evidence of disease recurrence or progression at the time of initial testing or throughout ctDNA monitoring. The first ctDNA time point was collected at a median of 33.1 months (range: 0.68-92 months) from baseline for these patients,a median of 3 time points was tested per patient (1-12). Of the remaining 9/60 patients, 3 (33%) had sustained ctDNA clearance for a median of 46 days (range: 0-224 days) in response to treatment, and 2 (22%) were initially ctDNA-negative but turned positive 105 and 156 days later, indicating potential resistance to treatment and molecular progression. Additional 4/9 (44%) had ctDNA levels consistently low levels (average: 0.42 mean tumor molecules/mL) while on treatment for a median of 260 days (range: 217-442) and showed no evidence of progression. Conclusions ctDNA status and dynamics correlate well with clinical status of patients with mILC, as determined by conventional monitoring tools such as imaging and biopsy. Our results indicate that personalized, tumor-informed, longitudinal ctDNA testing may serve as a useful tool for detection of progression and monitoring treatment response in mILC patients. Citation Format: Steffi Oesterreich, Antony Tin, Samuel Rivero-Hinojosa, Janie Fielder, Jenifer Ferguson, Ekaterina Kalashnikova, Angel Rodriguez, Minetta Liu, Adrian Lee. Personalized circulating tumor DNA testing for recurrence detection and treatment response monitoring in patients with metastatic invasive lobular carcinoma [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-13-12.

Abstract PO5-06-13: Impact of Therapy on Sites of Metastases in Triple Negative Breast Cancer

Abstract Background: Metastatic triple negative breast cancer (TNBC) is a diverse disease with the propensity to spread to visceral organs and the central nervous system (CNS). While systemic chemotherapy is commonly used, there is a growing utilization of immune checkpoint inhibitors (ICI) and antibody drug conjugates (ADC). However, few studies have examined the impact of specific therapies on individual metastatic sites, limiting clinical guidance for solitary metastases. Objective: This study aimed to evaluate the efficacy of various systemic therapies in TNBC patients with lung, liver, and CNS metastases. Methods: We analyzed data from the Dallas Metastatic Breast Cancer Study, a retrospective cohort study that includes all patients with metastatic breast cancer treated at a single academic medical center and identified 52 TNBC patients with visceral and CNS metastases diagnosed between 2009 and 2021. We correlated the site of metastasis with and treatment response, which was assessed based on imaging findings using RECIST 1.1 criteria. Results and Discussion: The median age at diagnosis of visceral metastatic disease was 52 years. Of the patients, 60% presented with de novo metastatic disease, while 40% experienced disease recurrence. The most prevalent metastatic sites were the lung (n=28), CNS (n=28), and liver (n=9). Among patients with detectable circulating tumor DNA, the most prevalent gene mutations in lung metastases were TP53 (36%), PTEN (13%), and PIK3R1 (10%). In liver metastases, TP53 (53%) and BRCA1 (15%) mutations were the most frequently observed. Similarly, in CNS metastases, TP53 (40%) and BRCA1 (13%) mutations were again most frequently detected. The notable frequency of TP53 mutations indicates the necessity for further investigations to explore potential differences in treatment approaches for patients with these mutations. The median overall survival (OS) was 14.43 months ±15.53, with the longest survival observed in patients with lung metastases (15 months), followed by liver metastases (6 months) and CNS metastases (5 months). Patients with involvement of a single visceral or CNS site had a mean OS of 15.80±18.19 months, whereas those with two sites of involvement had a mean OS of 13.08±10.18 months. Patients with metastases in all three sites had a mean OS of 8.33±8.50 months. Treatment modalities varied among patients. For liver metastases, chemotherapy (n=6), ICI (n=2), ADC (n=1), radiation therapy (n=2), and surgery (n=1) were administered. Lung metastases were treated with chemotherapy (n=26), ICI (n=4), ADC (n=5), radiation therapy (n=4), and surgery (n=1). CNS metastases were managed with chemotherapy (n=14), ICI (n=2), ADC (n=1), radiation therapy (n=21), and surgery (n=4). Systemic therapy for liver metastases resulted in stable disease (75%) and progressive disease (25%). In lung metastases, it led to stable disease (56%), partial response (23%), complete response (13%), and progressive disease (8%). CNS metastases treated with systemic therapy demonstrated stable disease (86%) and progressive disease (14%). The most commonly used systemic therapy was paclitaxel. Immunotherapy achieved a partial response (60%), stable disease (20%), and progressive disease (20%) in metastatic lesions. Treatment with ADCs resulted in stable disease (43%), partial response (29%), and progressive disease (29%). Compared to lung metastases, liver and CNS metastases exhibited lower response rates and overall survival. CNS metastases were less likely to receive systemic therapies, indicating a need for improvement. These findings highlight the importance of personalized treatment strategies tailored to individual metastatic sites in TNBC. Citation Format: Hannah Chang, Pallavi Dev, Luise Froessl, Shao-Po Huang, Christine Hodgdon, Julia Maues, Isaac Chan. Impact of Therapy on Sites of Metastases in Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-13.

Abstract PO3-22-06: Safety and efficacy of trastuzumab deruxtecan and concomitant radiation therapy in patients with metastatic HER2-positive breast cancer

Abstract Background Trastuzumab deruxtecan (T-DXd) currently represents the standard of care for the treatment of patients with metastatic HER2-positive (HER2+) breast cancer (BC) after disease progression in the first line, which includes taxanes and trastuzumab. This recommendation is based on the results of the DESTINY-Breast03 trial, which demonstrated improved efficacy compared to trastuzumab emtansine (T-DM1). Radiation therapy (RT) is frequently required in the metastatic setting, either for palliative purposes or with ablative intent in cases of oligometastatic or oligoprogressive disease. The aim of our study is to evaluate the safety of using T-DXd and concomitant radiation therapy (RT) in a consecutive series of HER2+ BC patients. Methods We conducted a retrospective evaluation of patients diagnosed with metastatic HER2+ BC who initiated treatment with T-DXd between May 2021 and May 2023 at our institution, with or without receiving RT. We collected clinical data pertaining to the diagnosis of metastatic disease, T-DXd treatment, acute toxicities, survival data, and biological characteristics of both the primary tumor and metastases. The primary objective of this study was to assess the association between RT and any adverse events greater than grade (G) 2. Results We retrospectively evaluated data from 30 consecutive patients who were treated with T-DXd, with or without RT. Among these patients, ten received RT either immediately before (within a month) or during T-DXd treatment, while the remaining 20 did not. The median age of the patients was 72 years (range 34-88), and the median follow-up period was 9 months. Thirteen patients received T-DXd as the fourth or subsequent line of systemic anti-HER2 treatment, eight patients received it as the third line, and seven patients received it as the second line. Two patients, who experienced early metastatic disease relapse (< 6 months after completion of adjuvant anti-HER2 therapy), received T-DXd as their first-line treatment. The median prescribed total dose of RT was 34 Gy (range 20-48), with a median number of fractions of 4 (range 2-10). The median equivalent dose in 2 Gy fractions (EQD2) was 64 Gy (range 23.3-104), and the median biologically effective dose (BED) was 76 Gy (range 28-125). The most commonly treated sites were bone (70% of cases), followed by brain (20%) and liver (10%). A chi-square test of independence was conducted to examine the relationship between the administration of RT and the development of toxicity exceeding G2. However, this analysis did not reveal a significant relationship (p = .27). Regarding the specific toxicities of interest associated with T-DXd, three cases of grade 3 fatigue were reported in the group that did not receive RT, while one case was observed in the RT group. Overall, only one case of grade 3 nausea was reported, and it occurred in the group that did not receive RT. G2 interstitial lung disease, which led to discontinuation of T-DXd, was observed in one case in the RT group and one case in the no-RT group. Conclusions Our initial data is promising regarding the potential safety of this combination, as it indicates that concurrent RT did not lead to an increase in severe acute toxicity. However, larger series of data are required to validate and confirm these findings. Citation Format: Luca Visani, Carlotta Becherini, Niccolo' Bertini, Ilaria Bonaparte, Luca Burchini, Carolina Orsatti, Marianna Valzano, Marco Banini, Viola Salvestrini, Erika Scoccimarro, Vieri Scotti, Isacco Desideri, Giulio Francolini, Lorenzo Orzalesi, Marco Bernini, Cinzia Tommasi, Jacopo Nori, Simonetta Bianchi, Icro Meattini, Lorenzo Livi. Safety and efficacy of trastuzumab deruxtecan and concomitant radiation therapy in patients with metastatic HER2-positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-22-06.

WNT5B drives osteosarcoma stemness, chemoresistance and metastasis.

Treatment for osteosarcoma, a paediatric bone cancer with no therapeutic advances in over three decades, is limited by a lack of targeted therapies. Osteosarcoma frequently metastasises to the lungs, and only 20% of patients survive 5 years after the diagnosis of metastatic disease. We found that WNT5B is the most abundant WNT expressed in osteosarcoma tumours and its expression correlates with metastasis, histologic subtype and reduced survival. Using tumor-spheroids to model cancer stem-like cells, we performed qPCR, immunoblotting, and immunofluorescence to monitor changes in gene and protein expression. Additionally, we measured sphere size, migration and forming efficiency to monitor phenotypic changes. Therefore, we characterised WNT5B's relevance to cancer stem-like cells, metastasis, and chemoresistance and evaluated its potential as a therapeutic target. In osteosarcoma cell lines and patient-derived spheres, WNT5B is enriched in stem cells and induces the expression of the stemness gene SOX2. WNT5B promotes sphere size, sphere-forming efficiency, and cell proliferation, migration, and chemoresistance to methotrexate (but not cisplatin or doxorubicin) in spheres formed from conventional cell lines and patient-derived xenografts. In vivo, WNT5B increased osteosarcoma lung and liver metastasis and inhibited the glycosaminoglycan hyaluronic acid via upregulation of hyaluronidase 1 (HYAL1), leading to changes in the tumour microenvironment. Further, we identified that WNT5B mRNA and protein correlate with the receptor ROR1 in primary tumours. Targeting WNT5B through inhibition of WNT/ROR1 signalling with an antibody to ROR1 reduced stemness properties, including chemoresistance, sphere size and SOX2 expression. Together, these data define WNT5B's role in driving osteosarcoma cancer stem cell expansion and methotrexate resistance and provide evidence that the WNT5B pathway is a promising candidate for treating osteosarcoma patients. WNT5B expression is high in osteosarcoma stem cells leading to increased stem cell proliferation and migration through SOX2. WNT5B expression in stem cells increases rates of osteosarcoma metastasis to the lungs and liver in vivo. The hyaluronic acid degradation enzyme HYAL1 is regulated by WNT5B in osteosarcoma contributing to metastasis. Inhibition of WNT5B with a ROR1 antibody decreases osteosarcoma stemness.

Detecting Metastatic Patterns of Oligometastatic Breast Cancer: A Comparative Analysis of 18F-FDG PET/CT and Conventional CT Imaging.

Metastasis-directed therapy has the potential to improve progression-free and overall survival in oligometastatic disease (OMD). For breast cancer, however, randomized trials have failed so far to confirm this finding. Because the concept of metastasis-directed therapy in OMD is highly dependent on the accuracy of the imaging modality, we aimed to assess the impact of 18F-FDG PET/CT on the definition of OMD in breast cancer patients. Methods: Eighty patients with a total of 150 18F-FDG PET/CT images (between October 2006 and January 2022) were enrolled in this retrospective study at the Technical University of Munich. The inclusion criteria were OMD, defined as 1-5 distant metastases, at the time of 18F-FDG PET/CT. For the current study, we systemically compared the metastatic pattern on 18F-FDG PET/CT with conventional CT. Results: At the time of 18F-FDG PET/CT, 21.3% of patients (n = 32) had a first-time diagnosis of metastatic disease, 40.7% (n = 61) had a previous history of OMD, and 38% (n = 57) had a previous history of polymetastatic disease. In 45.3% of cases, the imaging modality (18F-FDG PET/CT vs. conventional CT) had an impact on the assessment of whether OMD was present. An identical metastatic pattern was observed in only 32% of cases.18F-FDG PET/CT detected additional metastases in 33.3% of cases, mostly in the nonregional lymph node system. Conclusion: The use of 18F-FDG PET/CT had a substantial impact on the definition of OMD and detection of metastatic pattern in breast cancer. Our results emphasize the importance of establishing a standardized definition for imaging modalities in future trials and clinical practices related to metastasis-directed therapy in breast cancer patients.

Abstract CT090: DAREON™-7: A phase 1, open-label, dose escalation and expansion cohort trial of the delta-like ligand (DLL3)-targeting T-cell engager BI 764532, plus first-line platinum-based chemotherapy in patients with DLL3-positive (+) neuroendocrine carcinomas

Abstract Background Neuroendocrine carcinomas (NECs) have limited treatment options. DLL3 is highly expressed in NECs and is a promising treatment target. In an ongoing phase 1 trial (NCT04429087), BI 764532, a DLL3/CD3 IgG-like T-cell engager, was tolerable with clinical activity in patients with DLL3-positive (+) tumors, including those with small cell lung cancer and other NECs. Purpose DAREON™-7 (NCT06132113), a phase 1, open-label, dose-escalation (Part A) and dose-expansion (Part B) trial, aims to determine the maximum tolerated dose (MTD), recommended dose for expansion (RDE)/recommended phase 2 dose (RP2D), and the safety and efficacy of BI 764532 + platinum and etoposide in patients with DLL3+ NEC. Experimental design Part A: ~25 patients will receive intravenous BI 764532 (target dose after step-in dosing) plus carboplatin/etoposide (CE) until intolerable toxicity, or progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or for a maximum of 36 months. BI 764532 dose escalation will be guided by a Bayesian logistic regression model with overdose control. Part B: 2 cohorts (~15 patients each) will receive BI 764532 at the RDE/RP2D + CE or cisplatin/etoposide (carboplatin/etoposide or cisplatin/etoposide are the most-used standard of care [SOC] regimens). Key inclusion criteria: patients must have no prior systemic treatment for DLL3+ locally advanced or metastatic NEC (extrapulmonary or unknown primary) or large cell NEC of the lung except for 1 cycle of standard platinum/etoposide regimen as first-line treatment prior to entering the treatment period of the trial; patients with localized NEC or resectable disease who received prior adjuvant therapy can participate in the trial if they experienced a treatment-free interval of >6 months prior to the diagnosis of metastatic disease; and patients must have at least 1 measurable lesion as defined per RECIST v1.1. Patients must be adequate candidates to receive platinum/etoposide as the SOC treatment. Primary endpoints: occurrence of dose-limiting toxicities (DLTs) in the MTD evaluation (Part A) and on-treatment (Part B) periods. Secondary endpoints: occurrence of DLTs and adverse events during the on-treatment period (Part B), and efficacy measured by objective response and duration of response (Part B). Enrollment is ongoing. Citation Format: Jaume Capdevila, Timon Vandamme, Patricia Niccoli, Saori Mishima, Ken Kato, Yiyuan Ma, Ping Sun, Lijiang Geng, Ulrich M. Lauer. DAREON™-7: A phase 1, open-label, dose escalation and expansion cohort trial of the delta-like ligand (DLL3)-targeting T-cell engager BI 764532, plus first-line platinum-based chemotherapy in patients with DLL3-positive (+) neuroendocrine carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT090.